Structure Elucidation, Biosynthesis and Biological Evaluation of Neosorangicin A, a Member of the Sorangicin Family.

Antimicrobial resistance represents an escalating global health crisis, with drug-resistant infections predicted to cause up to 10 million deaths annually by 2050, underscoring the urgent need for novel antibiotics. Natural products play a crucial role in the discovery and development of antibiotics, with myxobacteria emerging as a particularly promising source due to their ability to produce structurally diverse and bioactive compounds. One prominent example of antibiotics from myxobacteria are the sorangicins, potent inhibitors of the bacterial RNA polymerase (RNAP). Here, we report the isolation of two unprecedented compounds, neosorangicin A (1) and neosorangioside A (2), from Sorangium cellulosum strain Soce439, elucidated their molecular structures, thereby revealing significant structural variation in comparison to sorangicin, and describe their biosynthetic pathway. Neosorangicin A (1) exhibited strong activity against various Gram-positive bacteria, including potent effects against Mycobacterium tuberculosis and enhanced efficacy on intracellular Staphylococcus aureus. In a murine wound infection model, a head-to-head comparison of neosorangicin A (1) and sorangicin A (3) provided useful insights into how the altered physicochemical properties, arising from the shortened side chain and the lack of the free carboxylic acid of neosorangicin A, influence the in vivo efficacy of sorangicin derivatives.